The hypothesis to be tested is that HIVAN is a disease in which HIV-1 infection of renal epithelium is required but not sufficient to induce the disease. Genetic factors responsible for susceptibility and progression are likely to be downstream of the viral entry event. To approach this, we propose to identify the QTL on mouse chr03 underlying the strain susceptibility of the murine model to develop HIVAN in the presence of an HIV-1 transgene, to identify additional modifying loci from other strains, and, in combination with Project #3, define candidate genes differentially expressed in response to HIV infection that are also located within mapped intervals. Furthermore, we hypothesize that pathogenesis derives from direct renal infection, expression of viral genes (specifically nef), induced expression of host genes, and interactions of nefwith host signaling pathways. Project #2 will define the relationship of HIV-1 infection of renal epithelium with the generation of phenotypic HIVAN, in contrast to other non-HIVAN but AIDS associated renal diseases. In addition, Project #2 will explore the compartments that harbor HIV-1, support its replication and genetic divergence, and consider the role that nef plays in pathogenesis. In addition, Project #2 will determine the impact of poymorphisms of the nef gene in phenotypic expression of HIVAN. Project #4 will explore the mechanisms by which nef activates intracellular signaling pathways in podocytes that lead to disease. Projects #2 and #4 will together address epitopes of nef that lead to a pathological signal cascade. Finally, Project #3 will address the role of aberrant host gene expression of podocytes and tubular epithelial cells in response to HIV infection. Together with Project #1, Project #3 will define potential candidate genes that define host susceptibiliity to HIVAN as well as define pathways of renal pathogenesis. Results from these studies will provide improved understanding of HIVAN pathogenesis, AIDS pathogenesis, appropriate strategies for therapy, and insights into renal disease susceptibility of Blacks in general.